Cyclization Pictet-Spengler

Ebumamonine was assembled utilizing a Pictet-Spengler cyclization of hydroxy-lactam 52 in the presence of trifluoroacetic acid at low temperature to give a mixture of diastereomers 53 in 95% yield. These compounds were readily separated by chromatography and the a-epimer was further elaborated to give the natural product. 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

Anionic domino processes are the most often encountered domino reactions in the chemical literature. The well-known Robinson annulation, double Michael reaction, Pictet-Spengler cyclization, reductive amination, etc., all fall into this category. The primary step in this process is the attack of either an anion (e. g., a carban-ion, an enolate, or an alkoxide) or a pseudo anion as an uncharged nucleophile (e. g., an amine, or an alcohol) onto an electrophilic center. A bond formation takes place with the creation of a new real or pseudo-anionic functionality, which can undergo further transformations. The sequence can then be terminated either by the addition of a proton or by the elimination of an X group. 

This strategy normally involves the generation of an iminium species from a tetrahydroisoquinoline and formaldehyde, followed by its Pictet-Spengler cyclization. It can be exemplified by the preparation of the berberine derivative 330 from tetrahydroisoquinoline 329 (Scheme 72) <2001JOC3495>. 

A recent formal synthesis of the alkaloid (—)-mitralactonine relied on a reaction that allowed the simultaneous creation of three new bonds, two of them a and one ft with respect to the quinolizine nitrogen. As shown in Scheme 112, treatment of triptamine with chiral aldehyde 480 in the presence of acid directly gave a mixture of diastereo-meric indoloquinolizidines 481 and 482 through a mechanism involving a Pictet-Spengler cyclization and a N-alkylation reaction <2007SL79>. 

Grieco and coworkers have independently described the same type of Pictet-Spengler cyclization reactions involving tryptophan methyl ester and aldehydes, but using methanol as solvent and hydrochloric acid as a catalyst (microwave irradiation, 50 °C, 20-50 min) [416], Moderate to good product yields were obtained. 

An interesting example of asymmetric induction has been used for the synthesis of (—)-l from L-tryptophan. Pictet-Spengler cyclization of the corresponding amide (127) with 5-chloropentanal afforded (—)-128 as the sole product. Removal of the unwanted carboxamide function was achieved in good yield by sodium borohydride reduction of die corresponding a-amino nitrile (—)-129, resulting in (—)-l (98). 

The total synthesis of ( )-geissoschizine (30) was reported by Yamada et al. (156) in 1974. The geometrically pure p-nitrophenyl ester 272 was condensed with tryptamine, and then the resulting amide 273 was transformed to lactam aldehyde 274 by hydroxylation with osmium tetroxide, metaperiodate oxidation, and Pictet-Spengler cyclization. 

A general strategy towards praziquantel derivatives 217 was developed by Liu et al. based on an Ugi four-component condensation (Ugi-4CR) followed by a Pictet-Spengler cyclization (PS-2CR) [66]. The variations of the groups and sub-stitutents in these scaffolds arise from the four starting materials isocyanide 218, aldehyde 219, amine 214, and carboxylic acid 220 (Scheme 39). This process produces ketopiperazine fused ring systems that mimic the scaffold of praziquantel. 

Combination of MCR with the Pictet-Spengler cyclization also leads to different types of scaffolds with ketopiperazine fused ring systems. Tetrahydro-jS-carboline scaffold 221 was prepared in a convergent, two-step procedure [67]. An array of indole derivatives was prepared by the reaction of tryptophan derivative 222, aldehyde 223, carboxylic acid 224, and bifunctional amine 214 (Scheme 40). 

The tetracyclic framework of homoberbine-like compound 210 was constructed by Beckmann rearrangement, reduction, and Pictet-Spengler cyclization (86JHC975). 

Treatment of enantiomerically pure tetrahydroisoquinolinecarboxylic acid, obtained from phenylalanine via Pictet-Spengler cyclization with two equivalents of /< /7-butyllithium in THF followed by alkylation gave the alkylated derivative as a single diastereomer6. 

Continuing the theme of small molecules as catalysts for organic reactions, Eric Jacobsen of Harvard has reported (J. Am. Chem. Soc. 2004,126, 10558) the design of a peptide thiourea that mediates enantioselective Pictet-Spengler cyclization, e.g. of 1 to 2. 

There are several routes to 3,4-dihydro-2/f- 1,2-benzothiazine dioxides (158), including the cyclization of aminosulfonic acids (157) or cyanosulfonamides (159). 3,4-Dihydro-IH-2,1-benzothiazine dioxides (161) are normally prepared by thermolysis of the sodium sulfonates (160) or aminosulfonamides (162) (71CB1880), and l//-3,4-dihydro-2,3-benzothiazine dioxides (164) are available either by a Pictet-Spengler cyclization of sulfonamides (163) with trioxane or of sulfonamide acids (165) with polyphosphoric acid (76CC470). 

The Pictet-Spengler cyclization of iminium salts, generated in situ from 3-indolyl)ethyl substituted amino acid esters 257 and various aldehydes, has been found to proceed with high stereoselectivity (up to 98.5 1.5)392. 

Stereoselective Pictet-Spengler cyclization of piperazine-1,4-dione 439 with MeCHO and EtCHO on the action of a 1-3 5 mixture of CF3C02H and... 

An alternative synthesis of ( )-a- and ( )--y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 6 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to ( )-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and Pictet-Spengler cyclization, ( )-y-lycorane (93) was obtained. A more efficient route to ( )-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119. 

An intramolecular [3 + 2] dipolar cycloaddition reaction has also been exploited in the design of a concise, stereospecific synthesis of ( )-a-lycorane (57) (119). Thus, cyclization of the azomethine ylide 145, which was produced in situ by the reaction of 144 with IV-benzylglycine, in refluxing toluene furnished the cw-hydroindole 146 as the exclusive product (Scheme 14). The transformation of 146 to racemic a-lycorane (57) was then achieved by N-debenzylation via catalytic, transfer hydrogenation and subsequent Pictet-Spengler cyclization. 

On another front, the mixture of allylic alcohols 512 and 513 was converted by reaction with methanesulfonic acid anhydride in the presence of triethylamine to a mixture of the corresponding mesylates, which were subjected collectively to methanolysis to afford 514, and none of the allylic ether epimeric at C-3 was isolated. N Debenzylation of 514 followed by a classic Pictet-Spengler cyclization then afforded ( )-buphanisine (361) (208). 

Silveira, C. C. Bemardi, C. R. Braga, A. L. Kaufman, T. S. Elaboration of 1-benzoyltetra-hydroisoquinoline derivatives employing a Pictet-Spengler cyclization with a-chloro a-phenylthio ketones. Synthesis of O-methyl-velucryptine. Tetrahedron Lett. 2001, 42, 8947-8950. 

Y.-H. Chu et al. described the application of a microwave-accelerated Pictet-Spengler reaction for the preparation of 1,1-disubstituted indole alkaloids [133] (Scheme 36). Most of the synthetic pathways concerning the Pictet-Spengler cyclization were performed with aldehydes or activated ke-... 

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